Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Chronic kidney disease (CKD) affects approximately 10% of the general population in the western world. Data from the UK and the US indicate that while the incidence of CKD is approximately 2% of the young adult population, it rises markedly with age reaching an incidence of 50% in the population aged over 75 years. These figures will increase as a consequence of the ageing of western populations and secondly from the increase in Type II diabetes flowing from the obesity epidemic. Most patients with Type II diabetes have evidence of renal damage, such as microalbuminuria, at the time of the diagnosis of their diabetes, and so an increase in the incidence of diabetes will automatically increase the incidence of early stage CKD. It will probably also increase the incidence of later stage CKD. A little over a decade ago diabetes ranked 3th or 4th as a cause for entry into renal replacement therapy programmes (dialysis and/or transplantation). While other causes have remained static or have increased only slightly, diabetes has increased to being the most common reason for entry into end stage renal failure programmes in less than a decade.
In CKD the progressive loss of renal function occurs as a consequence of the deposition of fibrous tissue between the functional units of the kidney or nephrons (interstitial fibrosis) as well as the ongoing replacement of the filtration surface by fibrous tissue (glomerular sclerosis). Some studies indicate that the former (interstitial fibrosis) may be more important than the latter (glomerular sclerosis) in determining whether a patient progresses to end stage. While primary glomerular damage is also important in the development of CKD and end stage renal disease (ESRD) there is evidence that increased interstitial fibrosis accelerates the loss of glomerular function by causing ischaemic damage to glomeruli—through collapsing the tufts and thickened capsules leading to obsolescence. Through this mechanism, interstitial fibrosis accelerates the progression of renal disease to end stage. Currently available treatments (such as ACE inhibitors, angiotensin receptor blockers, rennin inhibitors) alter glomerular haemodynamics reducing intraglomerular pressure thereby acting to stabilise glomerular sclerosis. In general they slow but do not prevent the progression of CKD. With an increasing prevalence of CKD clearly there is a substantial need to reduce the need for renal replacement therapy by preventing and/or reversing renal fibrosis.
VIP was discovered by Said and Mutt in the 1970's and has been shown to affect urinary sodium and bicarbonate excretion by the kidney. Systemic VIP administration also increases renin secretion by the kidney, which may be profibrotic as renin has recently been shown to have pro-inflammatory and pro-fibrotic properties. Acute VIP administration decreases glomerular filtration rate and renal plasma flow but the effects of chronic administration are not known. VIP administered prior to the insult has been shown to protect against acute renal failure, which occurs due to haemorrhage. However, the mechanisms involved in hypovolaemic acute renal failure (low perfusion pressure and hypoxia) are not contributory to the progression of CKD. Agents which lower blood pressure have been shown to slow the progression of chronic kidney disease by reducing intraglomerular pressure and thus decreasing the progression of glomerular sclerosis. VIP is a potent vasodilator, however unaided VIP does not lower blood pressure in the whole animal.
Conventional view of structure/function relationship with respect to VIP activity is that the N-terminal amino acid residues (1-5) are important and necessary for signal delivery once VIP binds to its receptor. Further, there are certain key amino acid residues throughout the VIP molecule, distal to the N-terminus, that are important for receptor binding. This would suggest that fragments of VIP lacking either the N-terminal residues or significant portions that encompass the receptor binding residues would not be fully functional.
Activity of VIP or fragments of VIP in the treatment of conditions such as kidney fibrosis, chronic kidney disease or kidney failure, has not been previously reported. Need currently exists for better and/or alternative treatments for such conditions.
It is therefore an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.